Antipsychotics (Part-4) FLUOROBUTYROPHENONES
The fluorobutyrophenones belong to a much-studied class of compounds, with many compounds possessing high antipsychotic activity. They were obtained by structure variation of the analgesic drug meperidine by substitution of the N-methyl by butyrophenone moiety to produce the butyrophenone analogue which has similar activity as chlorpromazine.
COOC2H5
N H3C
Meperidine
COOC2H5
N
O
Butyrophenone analog
The structural requirements for antipsychotic activity in the group are well worked out. General features are expressed in the following structure.
F
AR
Y O N
• Optimal activity is seen when with an aromatic with p-fluoro substituent • When CO is attached with p-fluoroaryl gives optimal activity is seen, although other groups, C(H)OH and aryl, also give good activity. • When 3 carbons distance separates the CO from cyclic N gives optimal activity. • The aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form. • AR is an aromatic ring and is needed. It should be attached directly to the 4-position or occasionally separated from it by one intervening atom. • The Y group can vary and assist activity. An example is the hydroxyl group of haloperidol.
The empirical SARs suggest that the 4-aryl piperidino moiety is superimposable on the 2-- phenylethylamino moiety of dopamine and, accordingly, could promote affinity for D2 receptors. The long N-alkyl substituent could help promote affinity and produce antagonistic activity.
Some members of the class are extremely potent antipsychotic agents and D2 receptor antagonists. The EPS are extremely marked in some members of this class, which may, in part, be due to a potent DA block in the striatum and almost no compensatory striatal anticholinergic block. Most of the compounds do not have the structural features associated with effective anticholinergic activity.
General formula of butyrophenone derivatives
F R
O
Haloperidol, (Haldol). 4-[4-(p-Chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone
OH F N
O
Haloperidol Cl
The compound is a potent antipsychotic useful in schizophrenia and in psychoses associated with brain damage. It is often chosen as the agent to terminate mania. Therapy for Gilles de la Tourette's syndrome often employs the drug. [Tourette's syndrome is a movement disorder characterized by facial tics, grimaces, strange uncontrollable sounds, and sometimes the involuntary shouting of obscenities. Overlay of dopamine and the antipsychotic drug haloperidol Software used: Dis Viewer Pro “Accelrys” [1]
Dopamine and Haloperidol after energy minimization
Haloperidol decanoate
CH CH O 2 3 8
O
F N
O
Haloperidol decanoate is a depot maintenance therapy injected every 4-6 weeks and appears to be as effective as daily orally administered haloperidol. Haloperidol decanoate
CH CH O 2 3 8
O
F N
O
Cl Haloperidol decanoate
Haloperidol decanoate is a depot maintenance therapy injected every 4-6 weeks and appears to be as effective as daily orally administered haloperidol.
Trifluperidol OH
F N
CF3 O
Trifluperidol
Droperidol, (Inapsine). 1-{1-[3-(p-Fluorobenzoyl)propyl]-1,2,5,6-tetrahydro-4-pyridyl}-2-benzimidazolinone
O
NH F N N
O
Droperidol
The agent may be used alone as a preanesthetic neuroleptic or as an antiemetic. Its most frequent use is in combination (Innovar) with the narcotic agent fentanyl (Sublimaze) preanesthetically. It is considered as a short-acting sedating butyrophenone and sometimes used in psychiatric emergencies as a sedative-neuroleptic.
Spiperone O
NH F N
O N
Spiperone
Spiperone contains spiro fusion between the peperidine moiety and imidazolidine ring. More details about spiperone are discussed with serotonin antagonists.
Metabolism of butyrophenones The following scheme shows typical oxidative metabolic pathway of butyrophenone as exemplified by haloperidol.
OH F N O
Haloperidol Cl Reduction N-dealkylation
OH HN OH F COOH + F N O OH Cl Cl
F COOH OH
F COOH N H O
Butyrophenpones structures:
F
AR
Y O N
OH F N O Haloperidol Cl
OH F N CF O 3 Trifluperidol
O
NH F N N O Droperidol
O
NH F N O N
Spiperone
Modified butyrophenone derivatives Modification of the haloperidol butyrophenone side chain by replacement of the p-fluorphenyl- keto- function with a di-(4-fluorophenyl)methane moiety results in diphenylbutylpiperidine neuroleptics, such as pimozide, penfluridol, and fluspirilene. Penfluridol modification of haloperidol or trifluperidol Pimozide modification of droperidol Fluspirilene modification of spiperone
OH F
CF N 3
Cl
Penfluridol
F
O OH F NH N N
Pimozide
F
F
O
N NH
N
F Fluspirilene
The diphenylbutylpiperidine class can be considered as a modification of the fluorobutyrophenone class. Because of their high hydrophobic character, the compounds are inherently long acting. All are effective in the control of schizophrenia. Pimozide has been shown to be useful in treating acute exacerbation of schizophrenia and in reducing rate of relapse in chronic schizophrenic patients. It is also used for treatment of Tourette's syndrome. Chronic treatment of Tourette's syndrome with pimozide or haloperidol carries the risk of producing potentially irreversible tardive dyskinesia. Overall, side effects for the compounds resemble those produced by the fluorobutyrophenones.